WO 95/10516, published Apr. 20, 1995, WO96/31478, published Oct. 10, 1996, and copending application Ser. No. 09/094687 filed Jun. 15, 1998 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase.
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT). The compounds of this invention are represented by the formula:
A compound of the formula: 
or a pharmaceutically acceptable salt or solvate thererof, wherein:
one of a, b, c and d represents N or N+Oxe2x88x92, and the remaining a, b, c and d groups represent CR1 or CR2; or
each of a, b, c, and d are independently selected from CR1 or CR2;
each R1 and each R2 is independently selected from H, halo, xe2x80x94CF3, xe2x80x94OR10 (e.g., xe2x80x94OCH3), xe2x80x94COR10, xe2x80x94SR10 (e.g., xe2x80x94SCH3 and xe2x80x94SCH2C6H5), xe2x80x94S(O)tR11 (wherein t is 0, 1 or 2, e.g., xe2x80x94SOCH3 and xe2x80x94SO2CH3), xe2x80x94N(R10)2, xe2x80x94NO2, xe2x80x94OC(O)R10, xe2x80x94CO2R10, xe2x80x94OCO2R11, xe2x80x94CN, xe2x80x94NR10COOR11, xe2x80x94SR11C(O)OR11, (e.g., xe2x80x94SCH2CO2CH3), xe2x80x94SR11N(R75)2 (provided that R11 in xe2x80x94SR11N(R75)2 is not xe2x80x94CH2xe2x80x94) wherein each R75 is independently selected from H or xe2x80x94C(O)OR11 (e.g., xe2x80x94S(CH2)2NHC(O)O-t-butyl and xe2x80x94S(CH2)2NH2), benzotriazol1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol5-ylthio such as 1-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, xe2x80x94OR10 or xe2x80x94CO2R10;
R3 and R4 are the same or different and each independently represents H, any of the substituents of R1 and R2, or R3 and R4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring (Ring III);
R5, R6, and R7 each independently represents H, xe2x80x94CF3, xe2x80x94COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)tR11, xe2x80x94NR10COOR11, xe2x80x94N(R10)2, xe2x80x94NO2, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R11, xe2x80x94CO2R10, OPO3R10, or R5 is combined with R6 to represent xe2x95x90O or xe2x95x90S; provided that for the groups xe2x80x94OR10, xe2x80x94SR10, and xe2x80x94N(R10)2R10 is not H;
R10 represents H, alkyl, aryl, or aralkyl (e.g., benzyl);
R11 represents alkyl or aryl;
X represents N, CH or C, and when X is C the optional bond (represented by the dotted line) to carbon atom 11 is present, and when X is CH the optional bond (represented by the dotted line) to carbon atom 11 is absent:
the dotted line between carbon atoms 5 and 6 represents an optional bond, such that when a double bond is present, A and B independently represent xe2x80x94R10, halo, xe2x80x94OR11, xe2x80x94OCO2R11 or xe2x80x94OC(O)R10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, xe2x80x94(OR11)2, H and halo, dihalo, alkyl and H, (alkyl)2, xe2x80x94H and xe2x80x94OC(O)R10, H and xe2x80x94OR10, xe2x95x90O, aryl and H, xe2x95x90NOR10 or xe2x80x94Oxe2x80x94(CH2)pxe2x80x94Oxe2x80x94wherein p is 2, 3 or 4;
R8 represents a heterocyclic ring selected from: 
xe2x80x83said heterocyclic rings (2.0 to 7.0 and 2.1 to 7.1) being optionally substituted with one or more substituents independently selected from:
(a) alkyl (e.g., methyl, ethyl, isopropyl, and the like),
(b) substituted alkyl wherein said substituents are selected from: halo, aryl, xe2x80x94OR15 or xe2x80x94N(R15)2, heteroaryl, heterocycloalkyl, cycloalkyl, wherein each R15 group is the same or different, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom, and wherein R15 is selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
(c) hydroxyl, with the proviso that carbon atoms adjacent to the nitrogen, sulfur or oxygen atoms of the ring are not substituted with hydroxyl;
(d) alkyloxy or
(e) arylalkyloxy;
(i.e., each substitutable H atom on each substitutable carbon atom in said heterocyclic rings is optionally replaced with substituents selected from (a) to (e) defined above);
Y represents CH2, NR16, O, S, SO, or SO2 wherein R16 is selected from: H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, aroyl, carbamoyl, carboxamido, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido and arylalkylsulfonamido;
n is 0 to 6 (preferably 1-3);
Q represents O or N, provided that Q is not adjacent to a heteroatom in the heterocycloalkyl rings of 2.1, 3.1, 4.1, 5.1, 6.1 and 7.1;
R12 is selected from: 
xe2x80x83(e.g., R12 is 9.0):
wherein R17 is selected from; (1) H, (2) alkyl, (3) aryl, (4) arylalkyl, (5) substituted arylalkyl wherein the substituents are selected from halo (e.g., F and Cl) or CN, (6) xe2x80x94C(aryl)3 (e.g., xe2x80x94C(phenyl)3, i.e., trityl), (7) cycloalkyl, (8) substituted alkyl (as defined above in (b)), or (9) cycloalkylalkyl;
R12A is selected from rings 8.0, 8.1 or 9.1, defined above;
said imidazolyl ring 8.0 and 8.1 optionally being substituted with one or two substituents, said imidazole ring 9.0 optionally being substituted with 1-3 substituents, and said pyridyl ring 9.1 optionally being substituted with 1-4 substituents, wherein said optional substituents for rings 8.0, 8.1, 9.0 and 9.1 are bound to the carbon atoms of said rings and are independently selected from: xe2x80x94NHC(O)R15, xe2x80x94C(R18)2OR19, xe2x80x94OR15, xe2x80x94SR15, F, Cl, Br, alkyl (e.g., methyl, such as 4-methyl in 9.0), substituted alkyl (as defined above in (b)), aryl, arylalkyl, cycloalkyl, or xe2x80x94N(R15)2; R15 is as defined above; each R18 is independently selected from H or alkyl (preferably xe2x80x94CH3), preferably H; R19 is selected from H or xe2x80x94C(O)NHR20, and R20 is as defined below;
R13 and R14 for each n are independently selected from: H, F, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl or xe2x80x94CON(R15)2 (wherein R15 is as defined above), xe2x80x94OR15 or xe2x80x94N(R15)2 provided that the xe2x80x94OR15 and xe2x80x94N(R15)2 groups are not bound to a carbon atom that is adjacent to a nitrogen atom, and provided that there can be only one xe2x80x94OH group on each carbon; and the substitutable R13 and R14 groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: F, alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heteroarylalkyl (i.e., the R13 and/or R14 groups can be unsubtituted or can be substituted with 1-3 of the substituents described above, except when R13 and/or R14 is H); or
R13 and R14, for each n, together with the carbon atom to which they are bound, form a C3 to C6 cycloalkyl ring;
R9 is selected from: 
R20 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocyloalkylalkyl, provided that R20 is not H when R9 is group 12.0 or 16.0;
when R20 is other than H, then said R20 group is optionally substituted with one or more (e.g., 1-3) substituents selected from: halo, alkyl, aryl, xe2x80x94OC(O)R15 (e.g., xe2x80x94OC(O)CH3), xe2x80x94OR15 or xe2x80x94N(R15)2, wherein each R15 group is the same or different, and wherein R15 is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom;
R21 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
when R21 is other than H, then said R21 group is optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl, aryl, wherein each R15 group is the same or different, and wherein R15 is as defined above; and
R22 is selected from cycloalkyl (e.g., cyclopropylmethyl, i.e., 
xe2x80x83heterocycloalkyl, aryl (e.g., phenyl), substituted aryl (e.g., halo as a substituent, such as F or Cl), alkyl (e.g., t-butyl), or substituted alkyl or substituted cycloalkyl (substituents include xe2x80x94OH, xe2x80x94CO2H, and xe2x80x94C(O)NH2).
Thus, in one embodiment of this invention R9 is 12.0. In another embodiment R9 is 13.0. In another embodiment R9 is 14.0. In another embodiment R9 is 15.0. In another embodiment R9 is 16.0.
The compounds of this invention: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described below.
This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of the tricylic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer and prostate cancer.
It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition or treatment being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.
The tricyclic compounds useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.
As used herein, the following terms are used as defined below unless otherwise indicated:
MH+xe2x80x94represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
BOCxe2x80x94represents tert-butyloxycarbonyl;
BOC-ONxe2x80x94represents 1-(tert-butoxycarbonyl)-2-tert-butyl-3-methyl-4-imidazolidinone nitrile;
CBZxe2x80x94represents xe2x80x94C(O)OCH2C6H5 (i.e., benzyloxycarbonyl);
CBZ-OSUCxe2x80x94represents benzyloxycarbonyl-O-succinimide;
CH2Cl2xe2x80x94represents dichloromethane;
CIMSxe2x80x94represents chemical ionization mass spectrum;
DEADxe2x80x94represents diethylazodicarboxylate;
DECxe2x80x94represents EDC which represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
DMFxe2x80x94represents N,N-dimethylformamide;
Etxe2x80x94represents ethyl;
EtOAcxe2x80x94represents ethyl acetate;
EtOHxe2x80x94represents ethanol;
HOBTxe2x80x94represents 1-hydroxybenzotriazole hydrate;
IPAxe2x80x94represents isopropanol;
iPrOHxe2x80x94represents isopropanol;
LAHxe2x80x94represents lithium aluminum hydride;
LDAxe2x80x94represents lithium diisopropylamide;
MCPBAxe2x80x94represents meta-chloroperbenzoic acid;
Mexe2x80x94represents methyl;
MeOHxe2x80x94represents methanol;
MSxe2x80x94represents mass spectroscopy;
NMMxe2x80x94represents N-methylmorpholine;
Phxe2x80x94represents phenyl;
Prxe2x80x94represents propyl;
TBDMSxe2x80x94represents tert-butyldimethylsilyl;
TEAxe2x80x94represents triethylamine;
TFAxe2x80x94represents trifluoroacetic acid;
THFxe2x80x94represents tetrahydrofuran;
Trxe2x80x94represents trityl;
alkylxe2x80x94represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms said cycloalkyl ring being optionally substituted with one or more (e.g., 1, 2 or 3) alkyl groups (e.g., methyl or ethyl) and when there is more than one alkyl group each alkyl group can be the same or different;
acylxe2x80x94represents a Gxe2x80x94C(O)xe2x80x94 group wherein G represents alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, xe2x80x94O-alkyl, xe2x80x94O-aryl, or NR25R26 wherein R25 and R26 are independently selected from alkyl or aryl;
arylalkylxe2x80x94represents an alkyl group, as defined above, substituted with an aryl group, as defined below, such that the bond from another substituent is to the alkyl moiety;
aryl-(including the aryl portion of arylalkyl)xe2x80x94represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted (e.g., 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, xe2x80x94C(O)N(R18)2, xe2x80x94SO2R18, xe2x80x94SO2N(R18)2, amino, alkylamino, dialkylamino, xe2x80x94COOR23 or xe2x80x94NO2, wherein R23 represents alkyl or aryl;
aroylxe2x80x94represents xe2x80x94C(O)aryl wherein aryl is as defined above (e.g., xe2x80x94C(O)phenyl);
cycloalkylxe2x80x94represents saturated carbocyclic rings of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms, said cycloalkyl ring optionally substituted with one or more (e.g., 1, 2 or 3) alkyl groups (e.g., methyl or ethyl) and when there is more than one alkyl group each alkyl group can be the same or different;
cycloalkylalkylxe2x80x94represents a cycloalkyl group, as defined above, substituted with an alkyl group, as defined above, such that the bond from another substituent is to the alkyl moiety;
haloxe2x80x94represents fluoro, chloro, bromo and iodo;
heteroaralkylxe2x80x94represents an alkyl group, as defined above, substituted with a heteroaryl group, as defined below, such that the bond from another substituent is to the alkyl moiety;
heteroarylxe2x80x94represents cyclic groups, optionally substituted with R3 and R4, having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, e.g., 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6-[1,2,4-triazinyl], 3- or 5-[1,2,4-thiadizolyl], 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl,2-, 3-, 4-, 5-, 6- or 7-indolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, triazolyl, 2-, 3- or 4-pyridyl or pyridyl N-oxide (optionally substituted with R3 and R4), wherein pyridyl N-oxide can be represented as: 
xe2x80x83heterocycloalkylxe2x80x94represents a saturated, branched or unbranched carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR24, wherein R24 represents alkyl, aryl, xe2x80x94C(O)N(R18)2, wherein R18 is as above defined (e.g., xe2x80x94C(O)NH2) or acyl-(suitable heterocycloalkyl groups include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, tetrahydropyranyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperazinyl, 2- or 4-dioxanyl, morpholinyl, etc.).
The positions in the tricyclic ring system are: 
The compounds of formula 1.0 include the 2R and 2S isomers shown below (2R is preferred): 
Examples of the optional substituents for the R12 or R12A moiety include: xe2x80x94CH3, xe2x80x94CH2OH, xe2x80x94CH2OC(O)O-cyclohexyl, xe2x80x94CH2OC(O)O-cyclopenity, ethyl, isopropyl, NH2, and xe2x80x94NHC(O)CF3.
Examples of R17 include: xe2x80x94C(O)NH-cyclohexyl, xe2x80x94C(phenyl)3, H, methyl or ethyl.
Examples of R20 include t-butyl, i-propyl, neopentyl, cyclohexyl, cyclopropylmethyl, 
Examples of R20 for group 12.0 include: t-butyl, ethyl, benzyl, xe2x80x94CH(CH3)2, xe2x80x94CH2CH(CH3)2, xe2x80x94(CH2)2CH3, n-butyl, n-hexyl, n-octyl, p-chlorophenyl, cyclohexyl, cyclopentyl, neopentyl, cyclopropylmethyl or 
Examples of R20 and R21 for 13.0 include: cyclohexyl, t-butyl, H, xe2x80x94CH(CH3)2, ethyl, xe2x80x94(CH2)2CH3, phenyl, benzyl, xe2x80x94(CH2)2phenyl, and xe2x80x94CH3.
Examples of R20 for 14.0 include: 4-pyridylNO, xe2x80x94OCH3, xe2x80x94CH(CH3)2, -t-butyl, H, propyl, cyclohexyl and 
Examples for R22 for 15.0 include: t-butyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, phenyl, substitued phenyl (e.g., halo, Such as F or Cl), 
Examples for R20 for 16.0 include: methyl, phenyl, isopropyl and cyclohexylmethyl.
Examples of R13 and R14 include: H, F, phenyl, xe2x80x94CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94(CH2)3CH3, benzyl, ethyl, p-chlorophenyl, and xe2x80x94OH (provided that that there can only be one OH on each carbon).
Cyclopropyl is an Example of the R13 and R14 group being taken together with the carbon atom to which they are bound to form a cycloalkyl ring.
R1, R2, R3, and R4 are preferably selected from H and halo, and are more preferably selected from H, Br, F and Cl. Representative compounds of formula 1.0 include trihalo, dihalo and monohalo substituted compounds, such as, for example: (1) 3,8,10-trihalo; (2) 3,7,8-trihalo; (3) 3,8-dihalo; (4) 8-halo; (5) 10-halo; and (6) 3-halo (i.e., no substituent in Ring III) substituted compounds; wherein each halo is independently selected. Preferred compounds of formula 1.0 include: (1) 3-Br-8-Cl-10-Br-substituted compounds; (2) 3-Br-7-Br-8-Cl-substituted compounds; (3) 3-Br-8-Cl-substituted compounds; (4) 3-Cl-8-Cl-substituted compounds; (5) 3-F-8-Cl-substituted compounds; (6) 8-Cl-substituted compounds; (7) 10-Cl-substituted compounds; (8) 3-Cl-substituted compounds; (9) 3-Br-substituted compounds; and (10) 3-F-substituted compounds.
Substituent a is preferably N or N+Oxe2x88x92 with N being preferred.
A and B are preferably H2, i.e., the optional bond is absent and the C5-C6 bridge is unsubstituted.
R5, R6, and R7 are preferably H.
X is preferably N or CH (i.e., the optional bond is absent), and more preferably X is N.
When one or more of the carbon atoms of the imidazole ring 8.0 or 9.0 are substituted, the substituents are generally selected from: xe2x80x94N(R15)2, xe2x80x94NHC(O)R15, xe2x80x94C(R18)2OR19, or alkyl, e.g., xe2x80x94CH3, xe2x80x94CH2OH, xe2x80x94CH2OC(O)O-cyclolhexyl, xe2x80x94CH2OC(O)O-cyclopentyl, ethyl, isopropyl, NH2, or xe2x80x94NHC(O)CF3.
R17 is preferably H or alkyl, most preferably H, methyl or ethyl, and more preferably methyl.
R20 in substituent 12.0 is preferably selected from: alkyl or cycloalkyl, most preferably t-butyl, isopropyl, neopentyl, cyclohexyl or cyclopropylmethyl.
R20 in substituent 13.0 is preferably selected from: alkyl or cycloalkyl; most preferably t-butyl, isopropyl or cyclohexyl. R21 is preferably selected from: H or alkyl; most preferably H, methyl or isopropyl; and more preferably H.
R20 in substituent 14.0 is preferably selected from: cycloalkyl or alkyl.
R22 in substituent 15.0 is preferably selected from: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, t-butyl, cyclopropylmethyl, 
and most preferably selected from: t-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
R20 in substituent 16.0 is preferably selected from: alkyl or cycloalkylalkyl; most preferably methyl, isopropyl or cyclohexylmethyl; more preferably methyl or isopropyl; and even more preferably methyl.
R13 and R14 are preferably selected from: H, F, Cl to C4 alkyl (e.g., methyl or isopropyl), xe2x80x94CON(R15)2 (e.g., xe2x80x94CONH2), xe2x80x94OR15 (e.g., xe2x80x94OH), aryl (e.g., phenyl) or arylalkyl (e.g., benzyl): or when R13 and R14 are taken together to form a cycloalkyl ring, said ring is preferably cyclopropyl cyclopentyl or cyclohexyl. Most preferably R13 and R14 are H.
For compounds of the invention, n is preferably 1-3, most preferably 1-2.
For compounds wherein R8 is ring 2.0 or 7.0, the xe2x80x94(CR13R14)nxe2x80x94R12 substituent can be in the 2-, 3- or 4-position relative to the ring nitrogen, provided that the xe2x80x94(CR13R14)nxe2x80x94R12 substituent is not in the 4-position when Y is O, S, SO or SO2. Preferably, the xe2x80x94(CR13R14)nxe2x80x94R12 substituent is in the 2- or 3-position, and most preferably in the 3-position. More preferably, the xe2x80x94(CR13 R14)nxe2x80x94R12 substituent is in the 2-position when n is 2, and in the 3-position when n is 1.
Compounds of formula 1.0, wherein X is N or CH, include, with reference to the C-11 bond, the R- and S-isomers: 
Compounds of this invention include the C-11 R- and S-isomers having the 2S stereochemistry.
Compounds of this invention include: 
Compounds of the invention also include compounds corresponding to 19.0-42.0 DD, except that Ring I is phenyl instead of pyridyl.
Compounds of the invention also include compounds corresponding to 19.0-42.0 DD except that Ring I is phenyl instead of Pyridyl, and the compounds have the 2S stereochemistry.
Compounds of this invention also include compounds corresponding to 19.0-42.0 DD except that the compounds have the 2S stereochemistry.
Compounds of formula 1.0 include compounds of formula 1.0(C) 
wherein R1 is H or halo (preferably Br, Cl or F), and R2 is H or halo (preferably Cl), and R9 is as defined for formula 1.0. Preferably. R1 is halo (most preferably Br, Cl or F), and R2 is H or halo (preferably Cl). Those skilled in the art will appreciate that compounds of formula 1.0(C) include compounds of formulas 1.0(D) to 1.0(G): 
Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms of any ring when more than one ring is present (e.g., ring 5.0).
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers, atropisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
The compounds of formula 1.0 can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
Compounds of the invention may be prepared according to the procedures described in WO 95/10516 published Apr. 20, 1995, WO96/31478 published Oct. 10, 1996, WO 97/23478 published Jul. 3, 1997, U.S. Pat. No. 5,719,148 issued Feb. 17, 1998, and copending application Ser. No. 09/094687 filed Jun. 15, 1998 (see also WO98/57960 Published Dec. 23, 1998); the disclosures of each being incorporated herein by reference thereto; and according to the procedures described below.
Compounds of the invention can be prepared according to the reaction schemes described below. 
The synthesis of the carboxylic acid (Scheme 1) begins with the differential protection (J. Med. Chem. (1994) 37, 3443-3451) of the piperazine dicamphorsulfonic acid salt (Helv. Chim. Acta, (1960) 117, 888-896) as illustrated in Scheme 2. Reaction of the distal amine with CBZ-OSuc at pH 11 followed by acylation with (BOC)2O gives the differentially protected acid. Hydrogenation over Pdxe2x80x94C selectively removes the CBZ group and the resulting amino acid was coupled with the desired tricyclic chloride. Compounds containing various functional groups can also be prepared by the different protection strategy shown in Scheme 3. except for the compounds wherein R20 is tert-butyl. 
Alternatively, the amine can be coupled to the di-BOC-protected acid intermediate prior to incorporation of the tricycle (Scheme 4). This derivative can be prepared from the di-CSA salt (Scheme 1) upon treatment of the salt with two equivalents (BOC)2O under basic conditions. Coupling of the desired amine to this intermediate under standard conditions (DEC, HOBT, NMM) gives the amide, which upon TFA-mediated removal of the BOC-protecting groups can be selectively alkylated by the desired tricyclic chloride (TEA, DMF, rt, 48 hours). At this stage, the free amine can be acylated, alkylated, or amidated under conditions obvious to one skilled in the art. When R=Br, chiral HPLC separation can be employed to readily resolve the C-11 diastereomers. 
Finally, the anhydride derivative can be opened with the appropriate amine (rt, CH2Cl2), followed by acylation, alkylation, or amidation of the resulting free amine. From there, a similar sequence as illustrated in Scheme 4 (Scheme 5) may be employed for the synthesis of the desired derivatives. 
The synthesis of the requisite amines are described generally in the following schemes. In each, one skilled in the art can appreciate the areas where synthetic generalities can be applied for the synthesis of a wider variety of compounds than those specifically illustrated.
The majority of the 2- and 3-substituted piperidine and pyrrolidine derivatives can be prepared through similar methods as illustrated in Scheme 6 beginning with the appropriate amino alcohol. Likewise, various imidazole derivatives may be prepared by employing the sodium salt of the desired imidazole derivative. This general scheme is not applicable where indicated i.e. piperidines with a 2-hydroxymethyl substitutent cannot be prepared using an N-carbamoyl protecting group due to the formation of undesired oxazolones. In these cases the NH must be protected as the N-benzyl or N-allyl derivative. 
Resolution of ethyl nipecotate with D- or L-tartaric acid (J. Org. Chem. (1991) 56, 1166-1170: Gazz. Chim. Ital. (1972) 102, 189-195.) gives the desired enantiomer which is converted to the free base by treatment with NaOH. Reduction of the acid with LAH followed by protection of the amine as the BOC derivative gives the alcohol. Treatment of the alcohol with p-toluenesulfonyl chloride in pyridine at 0xc2x0 C., followed by displacement with the sodium salt of the desired imidazole derivative and removal of the BOC-protecting group with Hcl/dioxane results in the desired amine as the hydrochloride salt.
The corresponding 2- and 3-substituted piperazine derivatives can generally be accessed through the anhydride (Scheme 5) as shown in Scheme 7. Ring opening of the anhydride with EtOH followed by reduction with NaBH4 gives the amino alcohol which can be converted to the N-substituted derivative by reductive amination with paraformaldehyde or another relevant aldehyde. Conversion to the desired imidazole derivative can be accomplished by displacement of the mesylate or tosylate with the sodium salt of the imidazole which upon removal of the BOC-protecting group gives the desired amine. 
The 3-pyrrolidinemethanol intermediates can be synthesized as shown in Scheme 8 (J. Med. Chem. 1990, 71-77). Treatment of the amine with the enoate gives a mixture of diastereomers which are readily separated by silica gel chromatography. Reduction of the amide with LAH and conversion to the imidazole derivative can be carried out as previously described. Catalytic hydrogenation gives the free amine. 
The 4-membered ring analogs can be synthesized as illustrated in Schemes 9 and 10. When the imidazole is directly attached to the ring, the sequence begins with mesylation of the alcohol followed by displacement with the sodium salt of the desired imidazole derivative. Removal of the benzhydryl protecting group is accomplished by catalytic hydrogenation. 
For 4-membered ring compounds with a methylene spacer between the imidazole and the ring, displacement of the mesylate with NaCN gives the nitrile which is readily hydrolyzed to the acid with NaOH and esterified under Fischer esterification conditions. The desired amine can be realized via transformations previously discussed. 
The morpholino side chains are prepared beginning with the epichlorohydrin as shown in Scheme 11 (Heterocycle, 38, 1033, 1994). Ring opening of the epoxide with benzyl amine followed by alkylation of the resulting amino alcohol gives the amide. Reduction of the amide with BH3 gives the morpholine into which the imidazole is incorporated by previously discussed methodology. Removal of the N-benzyl protecting group gives the desired amine.
Following the above procedure, but using the epichlorohydrin 
gives the amine 
Compounds with a 7-membered ring in the side-chain may be prepared as shown in Scheme 12. xcex1-Bromination of caprolactam followed by displacement with NaCN gives the nitrile. Methanolysis and subsequent reduction with LAH gives the amino alcohol which can easily be converted to the desired compound by previously described methodology. 
The 4-substituted piperidine-3-methanol derivatives can be synthesized as illustrated in Scheme 13. Protection of the carboxylic acid as the oxazoline also serves to activate the pyridine ring toward nucleoplhilic attack by MeLi. Rearomatization with sulfur, hydrolysis of the oxazoline, and esterification gives the ester which upon quaternization and reduction gives the enoate. Conjugate addition with MeI gives the 4,4-dimethyl derivative. This ester may be converted into the desired compound by previously described procedures. 
Those skilled in the art will appreciate that in Scheme 16 the wavy bond to H (xc2x152.0), xe2x80x94OCH3 (54.0a and 54.0b), xe2x80x94CN (55.0a and 55.0b), xe2x80x94COOH (56.0a and 56.0b), xe2x80x94COOH (57.0a, 57.0b, 58.0a and 58.0b) indicates that the band can be either  or  
Compound (xc2x1) 52.0 is resolved following procedures similar to those disclosed in WO97/23478 (published Jul. 3, 1997).
The reagents used in Reaction Scheme 3 are: Reaction Step a: Isatoic anhydride/methylene chloride; Reaction Step b: sodium nitrite/hydrochloric acid/methanol/cuprous chloride; Reaction Step c: (i) aq. hydrochloric acid/methanol/refux (ii) sodium hydroxide/sodium cyanide; Reaction Step d: conc. hydrochloric acid/reflux.; and Reaction Step e: di-tert.butyldicarbonate/-sodium hydroxide/tetrahydrofuran.
Compounds useful in this invention are exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.

To (R)-(xe2x88x92)-camphorsulfonic acid (2.5 kg) in distilled water (1250 mL) at 60xc2x0 C. was added a solution of the potassium salt of 2-carboxypiperazine (565 gm, 3.35 mol). The mixture was allowed to stir at 95xc2x0 C. until completely dissolved. The solution was cooled to room temperature and allowed to stand 48 hrs. The resulting precipitate was filtered to obtain a damp solid (1444 g). The solids were then dissolved in distilled water (1200 mL) and heated on a steam bath until all solids dissolved. The resulting solution was cooled slowly to room temperature and let stand 72 hrs. The crystalline solids were filtered to give a white crystalline solid (362 g), [xcex1]D=xe2x88x9214.9xc2x0.

The title compound from Preparative Example 1 (362 gm, 0.608 mol) was dissolved in distilled water (1400 mL) and methanol (1400 mL). 50% NaOH was added to the stirred reaction mixture until the pH reached xcx9c9.5. To this solution was added di-tert.butyldicarbonate (336 gm, 1.54 mol) portionwise. The pH of the reaction mixture was maintained at 9.5 with 50% NaOH (total of 175 ml), and the reaction mixture stirred for 2.5 hours to obtain a white precipitate. The reaction mixture was diluted with ice/water (9000 mL) and washed with Et2O (2000 mL). The Et2O was discarded and the pH of the aqueous layer adjusted to pH 3.0 by the portionwise addition of solid citric acid and extracted with CH2Cl2 (3xc3x972000 mL). The organic layers were combined, dried over Na2SO4, filtered and evaporated to give the title compound as a white glassy solid (201.6 g). FABMS: MH+=331.

To an ice cold solution DMF (49.6 ml) under a nitrogen atmosphere was added, dropwise, SOCl2 (46.7 ml) over a period of 5 minutes in a 5 L round bottom flask The reaction mixture was allowed to stir for 5 minutes, warmed to room temperature, and stirred 30 minutes. The resulting solution was cooled to 0xc2x0 C. and the title compound from Preparative Example 2 (201.6 gm, 0.61 mmol) in pyridine (51.7 mL) and CH3CN (1900 mL) was added via canulae. The resulting solution was warmed to room temperature to obtain a yellowish turbid solution and stirred 18 hours. The reaction mixture was filtered and the filtrate poured into ice water (7L) and then extracted with EtOAc (4xc3x972000 mL). The combined organics were dried over Na2SO4, filtered, and evaporated to dryness in vacuo to give the title product as a white solid (115.6 g 73% yield).

The title compound from Preparative Example 1 (17.85 gm, 30 mmol) was dissolved in distilled water (180 mL). Dioxane (180 mL) was added and the pH adjusted to xcx9c11.0 with 50% NaOH. The reaction mixture was cooled to 0-5xc2x0 C. in an ice-MeOH bath and a solution of benzylchloroformate (4.28 mL, 30 mmol) in dioxane (80 mL) was added over a period of 30-45 minutes while stirring at 0-5xc2x0 C. and keeping the pH at 10.5 to 11.0 with 50% NaOH. After the addition was complete, stirring was continued for 1 hr. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in distilled water (180 mL), the pH adjusted slowly to 4.0 with 1N HCl, and extracted with EtOAc (3xc3x97180 mL). The combined organics were dried over MgSO4, filtered, and evaporated to obtain the N,N-di-CBZ-2-carboxy-piperazine byproduct. The pH of the aqueous layer was adjusted to xcx9c10.5 with 50% NaOH and solid (Boc)2O (7.86 gm, 36 mmol) was added and the mixture was stirred while keeping the pH at xcx9c10.5 with 50% NaOH. After 1 hr. the pH stablized. The reaction was checked by tlc (30% MeOH/NH3/CH2Cl2) and if not complete, more (Boc)2O was added keeping the pH at xcx9c10.5. When reaction was shown to be complete by TLC, the reaction mixture was washed with Et2O (2xc3x97180 mL) (check that the product is not in the Et2O layer and dispose of the Et2O layer). The aqueous layer was cooled in an ice bath and pH to adjusted to 2.0 with 1N HCl (slowly) (get bubbling initially). The aqueous layer was extracted with EtOAc (3xc3x97200 mL) and the combined organics dried over MgSO4, filtered and evaporated in vacuo to obtain a white solid (9.68 g, 88% yield).

The title compound from Preparative Example 4 (9.6 gm, 26.3 mmol) was dissolved in absoluteEtOH (100 mL) in a hydrogenation vessel. The vessel was flushed with N2 and 10% Pd/C (3.0 g, 50% by weight with water) was added. The mixture was hydrogenated at 55 psi of H2 for 18 hours during which time a precipitate formed. When the reaction was complete (TLC, 30% MeOH/NH3/CH2Cl2), the reaction mixture was filtered through a pad of celite, and the pad washed with EtOH followed by distilled H2O. The filtrate was evaporated to xcx9c⅓ the volume and distilled H2O (200 mL) was added. The resulting solution was extracted with EtOAc (contains pure N,N-Di-Boc-2-carboxy-piperazine which was saved). The water layer was evaporated to dryness with azeotropic removal of residual H2O with methanol (2xc3x97) to give pure product (3.98 g).
4-(3-bromo-8-chloro-6, 11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-[(1,1-dimethylethoxy)carbonyl]-2(R)-piperazinecarboxylic acid 
The tricyclic alcohol 
(5.6 gm, 17.33 mmol) was dissolved in CH2Cl2 (56 mL) and SOCl2 (2.46 mL) was added while stirring under a dry N2 atmosphere. After 5 hrs. the tlc was checked (by adding an aliquot of the reaction mixture to 1N NaOH and shaking with CH2Cl2) and checking the CH2Cl2 layer by tlc using 50% EtOAc/Hexanes as the eluent). The mixture was evaporated to give a gum which was evaporated from dry toluene twice and once from CH2Cl2 to give a foamy solid. The resulting chloro-tricyclic compound was dissolved in dry DMF (100 mL) and the title compound from Preparative Example 5 (3.98 gm) was added followed by triethylamine (12.11 mL) and the mixture stirred at ambient temperature under a nitrogen atmosphere. After 24 hours. the reaction mixture was concentrated and the residue dissolved in EtOAc (200 mL) and washed with brine. The brine layer was extracted with EtOAc (2xc3x97) and the combined organics were dried over MgSO4, filtered, and evaporated to give a foamy solid. The solid was chromatographed on a 1xc2xdxe2x80x3xc3x9714xe2x80x3 column of silica gel eluting with 2L of 0.4% 7N MeOH/NH3:CH2Cl2, 6L of 0.5% 7N MeOH/NH3:CH2Cl2, 2L of 0.65% 7N MeOH/NH3:CH2Cl2, 2L of 0.8% 7N MeOH/NH3:CH2Cl2, 4L of 1% 7N MeOH/NH3:CH2Cl2, 2L of 3% 2N MeOH/NH3:CH2Cl2, 2L of 5% 2N MeOH/NH3:CH2Cl2, 2L of 10% 2N MeOH/NH3:CH2Cl2, 2L of 15% 2N MeOH/NH3:CH2Cl2, 4L of 20% 2N MeOH/NH3:CH2Cl2 to obtain 4.63 gm of final product.
Step A
Ref: Gazz. Chim. Ital. (1972) 102, 189-195; J. Org. Chem. (1991) 56, 1166-1170. 
Ethyl nipecotate (70.16 g, 0.446 mmol) and D-tartaric acid (67 g, 1.0 eq) were dissolved in hot 95% EtOH (350 mL). The resulting solution was cooled to room temperature and filtered and the crystals washed with ice-cold 95% EtOH. The crystals were then recrystallized from 95% EtOH (550 mL) to give the tartrate salt (38.5 g, 56% yield). The salt (38.5 g) was dissolved in water (300 mL) and cooled to 0xc2x0 C. before neutralizing with 3M NaOH. The solution was extracted with CH2Cl2 (5xc3x97100 mL) and the combined organics dried over Na2SO4 and concentrated under reduced pressure to give a clear oil (19.0 g, 89% yield). CIMS: MH+=158.
Step B 
LAH (118 mL, 1.0 M in Et2O, 1.0 eq.) was added to a solution of the title compound from Step A (18.5 g, 0.125 mmol) in THF (250 mL) at 0xc2x0 C. over 20 minutes. The resulting solution was warmed slowly to room temperature and then heated at reflux 2 hours. The reaction was cooled to room temperature and quenched by the slow addition of saturated Na2SO4. The resulting slurry was dried by the addition of Na2SO4, filtered through Celite and concentrated to give a colorless oil (13.7 g, 98% crude yield). CIMS: MH+=116; [xcex1]20D=xe2x88x928.4O (5.0 mg in 2 mL MeOH).
Step C 
The title compound from Step B (13.6 g, 0.104 mmol) was dissolved in MeOH (100 mL) and H2O (100 mL) and di-tert-butyl dicarbonate (27.24, 1.2 eq.) was added portionwise keeping the pH  greater than 10.5 by the addition of 50% NaOH. The reaction mixture was stirred at room temperature an additional 2.5 hours and concentrated in vacuo. The residue was diluted with H2O (350 mL) and extracted with CH2Cl2 (3xc3x97150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Flash chromatography using a 50% EtOAc in hexanes solution as eluent to give a white solid (12.13 g, 48% yield). FABMS: MH+=216; [xcex1]20D=+15.2 (5.0 mg in MeOH).
Step D 
p-Toluenesulfonyl chloride (12.75 g, 1.2 eq.) was added portionwise to the title compound from Step C (12.00 g, 55.74 mmol) in pyridine (120 mL) at 0xc2x0 C. The resulting solution was stirred 0xc2x0 C. overnight. The reaction mixture was diluted with EtOAc (300 mL) and washed with cold 1N HCl (5xc3x97300 mL), saturated NaHCO3 (2xc3x97150 mL), H2O (1xc3x97100 mL), brine (1xc3x97100 mL), and dried over Na2SO4 and concentrated in vacuo to give a pale yellow solid (21.0 g, 100% crude yield). FABMS: MH+=370.
Step E 
The title compound from Step D (21.0 g, 55.74 mmol) in DMF (300 mL) was treated with sodium imidazole (8.37 g, 1.5 eq.) and the resulting solution heated at 60xc2x0 C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with H2O (300 mL) and extracted with CH2Cl2 (3xc3x97150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using a 7% MeOH in CH2Cl2 solution as eluent to give a pale yellow solid (7.25 g, 49% yield). FABMS: MH+=266; [xcex1]20D=+8.0 (5.0 mg in MeOH).
Step F 
The title compound from Step E (5.50 g, 20.73 mmol) stirred at room temperature in 4M HCl in dioxane (50 mL) overnight. The resulting solution was concentrated and the residue triturated with Et2O to give a yellow solid (4.90 g, 99% yield). CIMS: MH+=166.

By essentially the same procedure set forth in Preparative Example 7 except using L-tartaric acid instead of D-tartaric acid in Step A, the title compound was prepared.
Step A 
A mixture of the piperazine anhydride (2.56 g, 10.00 mmol, 1.0 eq.) and sodium borohydride (965 mg, 25.00 mmol, 2.5 eq.) in absolute ethanol (50 ml) was gently refluxed under a nitrogen atmosphere for 48 h. The reaction volume was decreased to approximately 10 ml under house vacuum and diluted with brine (50 ml). The mixture was extracted with ethyl acetate (8xc3x9725 ml). The combined organic extracts were washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under house vacuum at 30xc2x0 C. The residue was flash chromatographed (CH2Cl2: 10% NH4OH/MeOH=17:1 v/v) over silica gel to give the title compound (1.09 g, 50%) as a light-yellow, viscous oil. EIMS: m/z 217 ([M+H[+, 46%), 161 (B+). HR-MS (FAB): Calculated for C10 H21N2O3 ([M+H]+): 217.1552. Found: 217.1549.
Step B
(Bhattacharyya, S. Tetrahedron Lett. 1994, 35, 2401.) 
A mixture of the title compound from Step A (1.09 g, 5.04 mmol, 1.0 eq.), paraformaldehyde (300 mg, .10.08 mmol, 2.0 eq.), and titanium isopropoxide (1.5 ml, 5.04 mmol, 1.0 eq.) in absolute ethanol (5 ml) was stirred at 70xc2x0 C. for 30 minutes and at room temperature for another 30 minutes. Sodium borohydride (195 mg, 5.04 mmol, 1.0 eq.) was added to the colorless solution. The solution was stirred at room temperature for 12 h and at 60xc2x0 C. for another 3 h. The solution was cooled to 0xc2x0 C. and treated with a 2.0 M aqueous ammonia solution (25 ml, 50.00 mmol, excess) to give a snow-white suspension. The suspension was filtered through a Celite 521 plugs and the filtrate was extracted with diethyl ether (4xc3x9725 ml). The ethereal extracts were combined and washed with brine (10 ml), dried over Na2SO4, filtered, and concentrated under house vacuum at 30xc2x0 C. The residue was flash chromatographed (CH2Cl2: 10% NH4OH/MeOH=9:1 v/v) over silica gel to give the title compound (1.10 g, 95%) as a light-yellow, viscous oil. MS (EI): m/z 231 ([M+H]+, 59%), 175(B+). HR-MS(FAB): Calculated for C11H22N2O3 ([M+H]+): 231.1709. Found: 231.1716.
Step C 
Methanesulfonyl chloride (296 xcexcl, 3.80 mmol, 1.25 eq.) was added dropwise to a stirred solution of the title compound from Step B (700 mg, 3.04 mmol, 1.0 eq.) and triethylamine (640 xcexcl, 4.56 mmol, 1.50 eq.) in anhydrous dichloromethane (5 ml) at 0xc2x0 C. under a nitrogen atmosphere. The resulting yellow suspension was stirred at 0xc2x0 C. for 1 h and at room temperature for another 3 h. The mixture was poured onto brine (25 ml) and extracted with dichloromethane (5xc3x9710 ml). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under house vacuum at 25xc2x0 C. to give a quantitative yield (940 mg) of crude mesylate, which was used directly in the next transformation (vide infra) without any attempts at characterization or purification.
A mixture of crude mesylate (940 mg, 3.05 mmol, 1.0 eq.) and sodium imidazole (608 mg, 6.08 mmol, 2.0 eq.) in anhydrous N,N-dimethylformamide (10 ml) was stirred at 60xc2x0 C. for 12 h under a nitrogen atmosphere. The brownish mixture was cooled to room temperature and diluted with brine (25 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (4xc3x9725 ml). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under house vacuum at 50xc2x0 C. The residue was flash chromatographed (CH2Cl2: 10% NH4OH/MeOH=19:1 v/v) over silica gel to give the title compound (432 mg, 1.54 mmol, 51%) as a thick, greenish oil. MS (EI): m/z 281 ([M+H]+, B+), 225 (79), 157 (91). HR-MS (FAB): Calculated for C14H25N4O2([M+H]+): 281.1978. Found: 28 1 11976.
Step D 
A solution of the title compound from Step C (400 mg, 1.43 mmol, 1.0 eq.) in anhydrous trifluoroacetic acid-dichloromethane (10 ml, 1:1 v/v) was stirred at room temperature under a nitrogen atmosphere for 12 h. The volatiles were removed under house vacuum at 40xc2x0 C. and the residue was redissolved in 2.0 M aqueous NaOH solution (10 ml). The volatiles were again removed under house vacuum, but at a bath temperature of 60xc2x0 C. The residue was flash chromatographed (CH2Cl2: 10% NH4OH/MeOH=6:4 v/v) over silica gel to give the title compound (136 mg, 0.76 mmol, 53%) as a thick, yellow oil. MS (EI): m/z 181 ([M+H]+, B+), 161 (76). HR-MS (FAB): Calculated for C9H17N4 ([M+H]+): 181.1453. Found: 181.1458.
Step A
N-Butoxycarbonyl-thiomorpholine 
Thiomorpholine (6 gm, 58 mmol) was dissolved in CH2Cl2 (200 mL) under a dry nitrogen atmosphere and the reaction mixture cooled in an ice bath. A solution of di-tert.butyl-dicarbonate (15.3 gm, 70 mmol) in CH2Cl2 (50 mL) was added dropwise and the reaction mixture stirred for 4 hours. The reaction mixture was washed with brine, followed by saturated NaHCO3, dried over MgSO4, filtered, and evaporated to obtain 14.37 gm of title product as a crystalline solid. mp=72.9-78.9xc2x0 C.
Step B
N-Butoxycarbonyl-thiomorpholinesulfone 
The title compound from Step A (16 gm, 78.7 mmol) was dissolved in 50% CH3OHxe2x80x94H2O (500 mL) at 0xc2x0 C. A slurry of Oxone(copyright) (72.6 gm, 118.05 mmol) was added portionwise while monitoring the pH at 10.5 with 25% NaOH. After 2 hours, the reaction mixture was filtered and the CH3OH was evaporated under reduced pressure. The residue was extracted with EtOAc 3 times to obtain 15.5 gm (84%) of title product as a crystalline solid. mp=157-159.2xc2x0 C.
Step C
N-Butoxycarbonyl-2-carboxyethyl-thiomorpholinesulfone 
The title compound from Step B (3.0 gm, 12.7 mmol) was dissolved in THF (30 mL). The reaction mixture was cooled to xe2x88x9278xc2x0 C. in a dryice acetone bath under a dry nitrogen atmosphere and 8.5 ml of a 1.5 Molar solution of lithium diisopropylamide in cyclohexane (LDA) was added dropwise and the solution stirred for xc2xd hour. Ethylchloroformate (1.83 mL, 19.05 mmol) was added dropwise and the solution stirred at xe2x88x9278xc2x0 C. for 1 hour. The temperature was allowed to rise to ambient and the reaction mixture stirred an additional 2 hours. The reaction mixture was added to brine and the product extracted three times with EtOAc to obtain 2.87 gm of crude product which was used in the next step without purification.
Step D
N-Butoxycarbonyl-2-hydroxymethyl-thiomorpholinesulfone 
The crude tile compound from Step C was dissolved in 30 ml of THF, cooled in an ice bath, and stirred. A 2M THF solution of Lithium borohydride (9 mL, 18 mmol) was added dropwise and the reaction mixture stirred for 3 hours. 1N HCl (xcx9c10 mL) was added slowly and the mixture stirred for 5 min. 1N NaOH (xcx9c20 mL) was added and the crude product extracted with ethylacetate, dried over magnesium sulfate, filtered, and evaporated to obtain a crude oil. The crude oil was chromatographed on silica gel using 20% ethyl acetate/hexanes to 40% ethylacetate/hexanes to obtain 0.88 gm of title product as a solid. mp=126.9-131.9xc2x0 C.
Step E
N-Butoxycarbonyl-2-imidazolylmethyl-thiomorpholinesulfone 
The title compound from Step D (0.56 gm, 2.14 mmol) and diisopropylethylamine(0.372 ml, 2.14 mmol) was dissolved in 5 mL of dichloromethane. Methanesulfonyl chloride (0.198 ml, 2.56 mmol) was added and the reaction mixture stirred under a dry nitrogen atmosphere for 30 min. The reaction mixture was added slowly to melted imidazole (2.9 gm, 20 eq.) at 120xc2x0 C. After the dichloromethane evaporated the reaction mixture was cooled to ambient to obtain a brown solid. The solid was dissolved in water and the product extracted with ethylacetate three times to obtain 0.449 gm of title product. mp=149.7-151.3xc2x0 C., FABMS (M+1)=316.2.
Step F
Preparation of 2-imidazolylmethyl-thiomorpholinesulfone 
The title compound from Step E (0.44 gm, 1.4 mmol) was dissolved in 5 ml of 4NHCl/dioxane and stirred for 1 hr. The mixture was evaporated to obtain 0.45 gm of title product.
Step A
N-Butoxycarbonyl-thiomorpholinesulfoxide 
N-Butoxycarbonyl-thiomorpholine from Preparative Example 10 Step A (7.07 gm, 58 mmol) was dissolved in 200 ml of dichloromethane. 50-60% mCPBA (13.7 gm, 80 mmol) was added portionwise over a period of 15 min. After 2 hours at ambient temperature the reaction mixture was washed with sat. sodium bisulfite, followed by sat. sodium bicarbonate, and the dried over magnesium sulfate, filtered, and evaporated to obtain 13.08 gm of a white solid. FABMS (M+1)=220.
Step B 
By essentially the same procedures set forth in Preparative Example 10 Step C-F, the title compound was prepared.

2-Methylimidazole (0.27 g, 1.3 eq.) was added to a solution of NaH (0.13 g, 1.3 eq., 60% in mineral oil) in DMF (5 mL) at room temperature and the resulting solution stirred 20 minutes before adding the title compound from Preparative Example 7 Step D (0.94 g, 2.54 mmol). The reaction mixture was heated to 60xc2x0 C. for 2 hours, cooled to room temperature and concentrated. The crude product was diluted with H2O (50 mL) and extracted with CH2Cl2 (3xc3x9775 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography using a 7% MeOH in CH2Cl2 solution as eluent to give a white solid (0.66 g, 93% yield). CIMS: MH+=280; [xcex1]20D=+4.9 (6.5 mg in 2.0 mL MeOH).
By essentially the same procedure set forth in Preparative Example 7 Step E, the following title compounds in Column 4 were synthesized beginning with the tosylate in column 2, using the imidazole derivative in Column 3, Table 1:

To the title compound from Preparative Example 13 (1.0 g, 3.58 mmol, 69:31 4-Me: 5-Me) in CH2Cl2 (10 mL) at 0xc2x0 C. was added TrCl (0.32 g, 1.05 eq. based on 5-Me). The resulting solution was stirred at 0xc2x0 C. for 2 hours and concentrated under reduced pressure. The crude mixture was purifed by flash chromatography using a 50% acetone in EtOAc solution as eluent to give the title compound as a clear oil (0.50 g, 72% yield). CIMS: MH+=280.

By essentially the same procedure set forth in Preparative Example 17, the title compound was prepared (0.49 g, 82% yield).
By essentially the same procedure set forth in Preparative Example 7 Step F except using the compounds prepared in Preparative Examples 12, 13, 14, 15, 16 (Column 2, Table 2), 16A, 16B, 16C, 16D, 17, 18, 71A (step D), 71A (step F) 16E, 72A, 74A, 75A and 76, the amine hydrochlorides in Column 3, Table 2 were prepared: